1-alkyl-1,2,5,6-tetrahydro-3-pyridylmethyl carboxylic

ABSTRACT

1-ALKYL-1,2,5,6-TETRAHYDRO-3-PYRIDYLMETHYL CARBOXYLIC ACID ESTERS OF THE FORMULA   WHEREIN R is selected from the group consisting of alkyl of two to 10 carbon atoms optionally substituted with cyano or alkoxy of one to seven carbon atoms, branched alkyl of three to five carbon atoms, alkenyl of two to three carbon atoms optionally substituted with a halogen, alkynyl of two to three carbon atoms, cycloalkyl of three to six carbon atoms and phenyl alkyl of one to seven alkyl carbon atoms, R1 is selected from the group consisting of hydrogen, methyl, -OH and C1-, R2 is selected from the group consisting of hydrogen, phenyl, cycloalkyl of five to six carbon rings and R1 and R2 together with the carbon to which they are attached form a five to six member cycloaliphatic ring, R3 is phenyl and when R2 and R3 are each phenyl they may optionally be linked together in the orthopositions by a direct bond or through an oxygen atom and their nontoxic, pharmaceutically acceptable acid addition salts and quaternary ammonium salts which compounds possess spasmolytic and central sedative properties without undesirable side effects usually associated with spasmolytics.

United States Patent [7 2] lnventors Hans-Hugo Hubner;

Gerhard Walther; Karl Z elle; llelmut Wick; Klaus Stockhaus, all of lngelhelm, Germany [21] Appl. No. 836,658 [22] Filed June 25, 1969 [45] Patented Dec. 14, 1971 [73] Assignee Boehrlnger lngelhelm G.m.b.ll.

lngelhelm, Germany [32] Priority June 25, 1968 [33] Austria [31] A6098/68 [54] l-ALKYL-l,2,5,6-TETRAHYDRO-3- PYRIDYLMETHYL CARBOXYLIC 8 Claims, No Drawings [52] U.S. Cl 260/295.5 R 260/294. R, 424/266 [51] lnt.Cl C07d 31/36 [50] Field of Search 260/295 R, 295.5 R, 294.8 R

[56] References Cited OTHER REFERENCES Benington et al., J. Org. Chem., Vol. 25, No. ll, pp. 1,912- 1,916,1960 QD241J.6

Burger, Medicinal Chemistry, Second Edition, lnterscience, pp. 497, 1960 RS 403 B- 8 1960 C7 Attorney-Hammond & Littcll ABSTRACT: l-alkyl-l ,2,5,6-tetrahydro-3pyridylmethyl carboxylic acid esters of the formula I bon atoms, cycloalkyl of three to six carbon atoms and phenyl alkyl of one to seven alkyl carbon atoms, R, is selected from the group consisting of hydrogen, methyl, OH and Cl-, R is selected from the group consisting of hydrogen, phenyl, cycloalkyl of five to six carbon rings and R, and R together with the carbon to which they are attached form a five to six member cycloaliphatic ring, R;, is phenyl and when R and R are each phenyl they may optionally be linked together in the orthopositions by a direct bond or through an oxygen atom and their nontoxic, pharmaceutically acceptable acid addition salts and quaternary ammonium salts which compounds possess spasmolytic and central sedative properties without undesirable side effects usually associated with spasmolytics.

l-ALKYL-l,2,5,ti-'I'E'IRAI-IYDRO-3-PYRID CARBOXYLIC OBJECTS OF THE INVENTION It is an object of the invention to provide the novel carboxylic acid esters of the formula I and their acid addition and quaternary ammonium salts.

It is another object of the invention to provide novel processes for the preparation of the carboxylic acid esters of the formula I.

It is a further object of the invention to provide novel spasmolytic compositions.

It is an additional object of the invention to provide a novel method of treating spasms in warrnblooded animals.

These and other objects and advantages of the invention will become obvious from the following detailed description.

THE INVENTION The novel compounds of the invention are selected from the group consisting of l-alkyll ,2,5,6-tetrahydro-3-pyridylmethyl carboxylic acid esters of the formula wherein R is selected from the group consisting of alkyl of two to carbon atoms optionally substituted with cyano or alkoxy of one to seven carbon atoms, branched alkyl of three to five carbon atoms, alkenyl of two to three carbon atoms optionally substituted with a halogen,"alkynyl of two to three carbon atoms, cycloalkyl of three to six carbon atoms and phenyl alkyl of one to seven alkyl carbon atoms, R, is selected from the group consisting of hydrogen, methyl, OH and Cl-, R, is selected from the group consisting of hydrogen, phenyl, cycloalkyl of five to six carbon rings and R, and R, together with the carbon to which they are attached form a five to six member cycloaliphatic ring, R, is phenyl and when R, and R are each phenyl they may optionally be linked together in the orthopositions by a direct bond or through an oxygen atom and their nontoxic, pharmaceutically acceptable acid addition salts and quaternary ammonium salts.

Examples of suitable acids for the formation of the nontoxic, pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., and organic acids such as oxalic acid, citric acid, tartaric acid, fumaric acid, maleic acid, acetic acid, propionic acid, butyric acid, methane sulfonic acid, succinic acid, etc.

The quaternary ammonium compounds may be prepared by reacting a compound of the formula I with a lower alkyl or aralkyl halide or dialkyl sulfate. Examples of suitable agents are ethyl bromide, ethyl chloride, butyl bromide, phenethyl bromide, methane sulfonate, etc.

The novel products of the invention are preferably used in the form of their acid addition salts or quaternary ammonium salts. Examples of specific compounds of the formula I are lethyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, 1 -isopropyll ,2,5,otetrahydro-li-pyridylmethyl benzilic acid ester, l-n-butyll ,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, l-n-amyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, l-isoamyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, l-n-hexyl-l,2,5,6-tetrahydro-3- pyridylmethyl benzilic acid ester, l-n-heptyl-l,2,5,6- tetrahydro-3-pyridylmethyl benzilic acid ester, l-n-octyll,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, l-nnonyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, l-n-decyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, l-(fi-cyanoethyD- l ,2,5,6-tetrahydro-3-pyrldyl-methyl benzilic acid ester, l'(B-methoxyethyD-l,2,S,6tetrshydro-3- pyridylmethyl benzilic acid ester, l-cyclopropyl-l,2,5,6- tetrahydro-3-pyridylrnethyl benzilic acid ester, l-allyl- 1 ,2,5,6- tetrahydro-B-pyridylmethyl benzilic acid ester, l-(3-chloroallyl)-l,2,5,6-tetrahydro-3-pyridyl-methyl benzilic acid ester, 1- propargyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester, l-phenethyl-l,2,5,6-tetrahydro-3-pyridylrnethyl benzilic acid ester, l-ethyl-l,2,5,6-tetrahydro-3-pyridylmethyl acyclopentyl-a-phenyl-acetic acid ester, l-ethyl-l,2,5,6- tetrahydro-3-pyridylmethyl a-cyclohexyl-a-phenybacetic acid ester, l-ethyl-l,2,5,6-tetrahydro-3-pyridylmethyl l '-phenylcyclopentane carboxylic acid ester. l-ethyl-l,2,5,6- tetrahydro-3-pyridylmethyl hexahydro-benzilic acid ester.

The novel carboxylic acid esters of the formula 1 may be produced by either of the following two procedures:

a. by esterification of a compound of the formula wherein R has the above meaning and X is hydroxy or a halogen atom with a compound of the formula wherein R,, R, and R, possess the above meanings and Y is hydroxy or an alkoxy group or a metal, or with another derivative of this compound suitable for esterification, according to known methods, as described for example in Houben-Weyl, Methoden der Organischen Chemie, Vol. III, pg. 508,( 1952) or b. by alkylation of an ester of the formula wherein R R and R, have the above meanings, at the nitrogen atom of the tetrahydropyridine ring, according to known processes, as for example described in Houben- Weyl, Methoden der Organischen Chemie, Vol. XI] 1 pg. 3 (1957).

The final products of the formula 1 can be reacted with an aqueous acid to form the corresponding acid addition salt or converted into a quaternary ammonium salt by known procedures.

The esterification of a compound of the formula II is preferably performed using a customary esterification agent, such as an acyl halide or anhydride or by reacting a compound of formula ll, wherein X is a halogen atom, with a salt of a carboxylic acid of the formula III. Furthennore, the reaction of an acid ester of the formula III (Y=O-alkyl) with a carbinol of the formula II (X=0l-l) has proved to be especially suitable.

The compounds of the formula ll used as starting materials for process (a) are also novel and they may, for instance, be produced by alkylation of a 2,3,5,6-tetrahydropyridine-3-carboxylic acid alkyl ester at'the nitrogen atom and subsequent reduction of the ester, such as with aluminum lithium hydride, or by reduction of a quaternary pyridylcarbinol of the formula also be obtained by reaction of a secondary amine of the formula W with an aldehyde in the presence of formic acid.

The l,2,5,6-tetrahydro-3-pyridylmethyl carboxylic acid esters of the formula IV used as starting materials in process (b) are also novel compounds and they may, for instance, be obtained by ester exchange of l,2,5,6-tetrahydro-3-pyridylmethyl alcohol with an ester, preferably the methyl ester, of the desired acid of the formula 111 (Y= Oll'l).

The novel spasmolytic compositions of the invention are comprised of small but effective amounts of at least one compound of the formula I or its acid additions or quaternary ammonium salts and a major amount of a pharmaceutical carrier. The compositions may be in the form of pills, tablets, sugarcoated tablets, ointments, suppositories, solutions, injectable solutions and suspensions, etc. The usual useful dose is 0.1 to 50, preferably 1 to 5 mg., and they may contain other therapeutic agents such as hypnotics or tranquilizers.

The novel compositions of the invention have spasmolytic and central sedative properties. They not only have the same degree of activity as the knownspasmolytic, atropine, but they incorporate a novel type of spasmolytic activity as side efiects such as mydriasis, tachycardia and partially also inhibition of secretion, at present considered as being unavoidable for such substances, are practically completely missing. In particular, they have an extraordinarily favorable ratio of the desired spasmolytic action and the undesirably mydriatic side effect. In the animal test, lacrimation and salivation remained uninfluenced as well in the applied doses.

As no tachycardia was observed as well, and as with some of the novel compounds the gastric fluid inhibiting effect of atropine is practically completely absent as well, all the undesirable side effects of atropine are nearly eliminated with the compounds according to the invention.

Among the preferred-compounds of formula 1 proven to be especially effective, are those where R represents an alkyl group with two to six carbon atoms or allyl, R, is hydroxy and R, and R, are phenyl groups.

The novel method of treating spasms in warmblooded animals comprises administering to warmblooded animals a safe and effective amount of at least one compound of the formula l or an acid addition salt or quaternary ammonium salt thereof. The compounds may be administered orally, rectally or transcutaneously. The usual useful daily dose is 0,005 to 2,5 mgJkg. depending upon the mode of administration and the particular compound.

in the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

EXAMPLE 1 PREPARA'IION OF l-n-l-lexyll .2,5,6-tetrahydro3- Pyridylmethyl benzilic acid ester STEP A: l-n-hexyll ,2,5 ,6-tetrahydro-3-pyridyl-carbino1 22.5 g. (0.1 mol) of l-n-hexyl-1,2,5,6-tetrahydronicotinic acid methyl ester (b.p.=-95 C. at 0.01 mm. Hg) were dropped over 1 hour while stirring into a solution of 2.1 g. (0.55 mol) of LiALl-L in 200 ml. of absolute ether. After 2 hours of heating at reflux, the mixture was cooled off and excess LiAll-L was decomposed cautiously with 10 ml. of water. The mixture was centrifuged for a further hour and the ether solution was filtered. The residue was washed several times with small portions of ether and the filtrate was finally evaporated in vacuo at 40 C. maximum. The sirupy residue was distilled in high vacuo to obtain 16.5 g. (84 percent yield) of l-n-hexyl-l,2,5,6-tetrahydro-3-pyridyl-carbinol as a colorless oil having a boiling point of l 15-420 C. at 0.5 mm. Hg. STEP B: l-n-hexyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester 19.7 g. (0.10 mol) of l-n-hexyl-l,2,5,6-tetrahydro-3- pyridyl-carbinol and 26.6 (0.1 1 mol) of methyl ester of benzilic acid were dissolved successively in ml. of absolute nheptane at 80 C. After addition of 1 ml. of sodium methylate solution (4.6 g. of sodium in 100 ml. of methanol), the mixture was refluxed for 2 hours and the split off methanol was recovered in the water separator. After the reesterification was finished, the solution at approx. 80 C. was filtered over activated charcoal and evaporated under the waterjet vacuo to obtain 37 g. (73 percent yield) after recrystallization from isopropyl ether of l-n-hexyl-l,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester with a melting point of 5758 C. The hydrobromide salt thereof had a melting point of C., the methane sulfonate thereof had a melting point of 141- 142 C. and the bromomethylate derivative melted at 205- 206 C.

EXAMPLE la 109.12 g. (1 mol) of 3-pyridy1 carbinol and 173.33 g. (1.05 mol) of n-hexylbromide were dissolved in 400 m1. of methanol and the solution was heated to 60 C. within a sealed vessel for 3 days. into the solution diluted with 2.4 liters of methanol, there was added over 50 minutes at 15 C. while stirring 62.4 g. (1.65 mol) of NaBl-L. The reaction solution was stirred for 75 minutes and then evaporated in vacuo at a bath temperature of 60 C. The residue was divided between 1.5 liters of ether and 550 ml. of water and the aqueous phase was once more extracted with 500 ml. of ether. The united ether phases were filtered over coal and after drying over anhydrous Na,S0 were evaporated under reduced pressure to obtain 178.3 g. (90.3 percent of theory) of crude 1-n-hexy1-1,2,5,6- tetrahydro-3-pyridylcarbinol which maybe used for esterit'rcation without further purification.

EXAMPLE 11 1 -lsoamyll ,2,5,6-tetrahydro' 3-pyridy1methyl benzilic acid ester 18.4 g. (0.1 mol) of l-isoamyl-l,2,5,6-tetrahydro-3-pyridyl carbinol and 10.2 g. (0.1 mol) of absolute triethylamine were dissolved in 100 ml. of absolute benzene. While cooling externally with ice-water and stirring, a solution of 26.5 g. (0.1 mol) of a,a-diphenyl-a-chloroacetylchloride in 100 ml. of absolute benzene was added to this solution within 20 minutes. Stirring was continued for 1 hour at room temperature and the triethylammonium chloride was filtered off and the solution was evaporated in vacuo. The oil residue was boiled in 200 m1. of distilled water. After a clear solution has formed (approx. 3

minutes),itwasadjustedtoaplivalueof5to6with2N hydrochloric acid, cooled and extracted several times with small portions of ether. The aqueous phase was made alkaline with sodium bicarbonate solution and extracted three times with 50 ml. of ether. After drying over K,CO,, the ether was evaporated oil and the resulting residue of l-isoamyl-l,2,5,6- tetrahydro-3-pyridyhnethyl benzilic acid ester was dissolved in 60 ml. of alcohol and converted with alcoholic hydrochloric acid (pH 3 to 4) into the hydrochloride salt. The alcoholic solution was filtered over activated charcoal and ether was added until the solution became turbid. 19 g. (43 percent yield) of the hydrochloride of l-isoamyl-1,2,5,6-tetrahydro-3- pyridylmethyl benzilic acid ester having a melting point of 151-152 C. were obtained.

EXAMPLE 111 l -n-1-lexyll ,2,5 ,6-tetrahydro-3-pyridylmethylbenzilic acid ester methane sult'onate 32.34 g. (0.1 mol) of 1,2,5,6-tetrahydro-3-pyridylmethyl benzilate and 18.2 g. (0.11 mol) of l-n-bromo-hexane in 75 ml. of absolute benzene were refluxed in the presence of 11.1 g. (0.11 mol) of absolute triethylamine for 5 hours and the mixture was then allowed to rest for hours at room temperature. The crystallized triethylammonium bromide was filtered off and the filtrate was evaporated as far as possible under waterjet vacuo at an exterior temperature of 50 C. maximal. The residue was dissolved in 50 ml. of alcohol and the resulting solution was adjusted with methane sulfonic acid to a pH of 2. By adding ether thereto until turbidity occurred, there were obtained 31 g. (61.5 percent yield) of l-n-hexyl- 1,2,5,6-tetrahydro-3-pyridyl methyl benzilic acid ester methane sulfonate melting at l4l-l42 C. The bromoethylate of the said ester had a melting point of l77-178 C. and the bromobutylate had a melting point of 144-145 C.

EXAMPLE 1V 1-( fl-MethoxyethyD-l ,2,5,6-tetrahydrt 3-pyridylmethy1 benzilic acid ester hydrochloride 32.3 g. (0.1 mol) of l,2.5,6-tetrahydro-3-pyridylrnethyl benzilate were dissolved in a mixture of 75 ml. of tetrahydrofuran and 30 ml. of dimethylformamide while heating to approx. 50 C. and then 16.8 g. (0.2 mol) of anhydrous sodium bicarbonate were added thereto. While stirring and heating at reflux, 15.3 g. (0.11 mol) of 2-(fi-bromoethyl)- methylether, dissolved in 15 ml. of tetrahydrofuran and 6 ml. of dimethylformamide were dropped into the solution. After refluxing for 4 hours, the inorganic material was filtered oh and the filtrate was evaporated as faras possible in the boiling water bath. The residue was dissolved in 300 ml. of benzene, filtered over activated charcoal and evaporated again. The residue was purified over aluminum oxide (activity step 111) and then on a silica gel column, with ethyl acetate as solvent system. The eluates were evaporated under waterjet vacuo at a bath temperature of 50 C. to obtain 20.15 g. (54.4 percent of theory) of 1 -(fi-methoxyethyl)-l ,2,5,6 tetrahydro-3- pyridylmethyl benzilic acid ester. Its hydrochloride melted at l45-146 C.

EXAMPLE V l-Ethyl-l ,2,5,6-tetrahydro 3-pyridylmethyl a-cyclopentyl-a-phenyl-acetic acid ester Into a solution of 14.1 g. (0.1 mol) of l-ethyl-l,2,5,6- tetrahydro-3-pyridylcarbinol and 10.2 g. of absolute triethylamine in 100 ml. of anhydrous benzene, a solution of 22.3 g. (0.1 mol) of a-cyclopentyl-a-phenyl-acetic acid chloride in 100 ml. of absolute benzene were dropped over 30 minutes while stirring and cooling. The solution was stirred for another 2 hours at room temperature, and the precipitated triethylammonium chloride was filtered and the benzene solution was evaporated in vacuo. The residue was mixed with water. made weakly acidic with 2 N hydrochloric acid and extracted twice with little ether. The acid solution was made alkaline with Nal-ICO, and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude l-ethyl-l ,2,5,6-tetrahydro-3-pyridylmethyl a-cyclopentyl-a-phenyl-acetic acid ester was converted into its hydrochloride in the usual way and by recrystallization hem acetonitrile/ether, 23 g. (63.4 percent of theory) of the analytically pure hydrochloride salt melting at 166- 168 C. were obtained.

EXAMPLEVI Using the procedure of example 1, 1-ethyl-1,2,5,6- tetrahydro-3-pyridyl methyl benzilic acid ester hydrochloride having a melting point of 163 C. was obtained.

EXAMPLE VII Using the procedure of example 1, l-ethyl-l,2,$,6- tetrahydro-3-pyridylmethyl benzilic acid ester bromoethylate having a melting point of 190-191 C. was obtained.

EXAMPLE VIII Using the procedure of example 1, 1-n-propyl-1,2,5,6- tetrahydro3-pyridylmethyl benzilic acid ester hydrochloride having a melting point of 131 C. was obtained.

EXAMPLE IX EXAMPLE X Using the procedure of example 1, 1-nbutyl-1,2,5,6- tetrahydro-3-pyridylrnethyl benzilic acid ester hydrochloride having a melting point of 143 C. was obtained.

EXAMPLE Xl Using the procedure of example 1, l-n-pentyl-l,2,5,6- tetrahydro-3-pyridylmethyl benzilic acid ester hydrochloride having a melting point of 150 C. was obtained.

EXAMPLE X11 Using the procedure of example 1, l-n-heptyl-l,2,5,6- tetrahydro-B-pyridylmethyl benzilic acid ester hydrochloride having a melting point of 140 C. was obtained.

EXAMPLE XIII Using the procedure of example I, l-n-octyl-1,2,5,6- tetrahydro-3-pyridylmethyl benzilic acid ester hydrobromide having a melting point of C. was obtained.

EXAMPLE XIV Using the procedure of example 1, l-n-nonyl-l,2,5,6- tetrahydro-3-pyridylmethyl benzilic acid ester hydrobromide having a melting point of 124 C. was obtained.

EXAMPLE XV Using the procedure of example 1, l-n-decyl-l,2,5,6- tetrahydro-S-pyridylmethyl benzilic acid ester hydrochloride having a melting point of 127 C. was obtained.

EXAMPLE XVI Using the procedure of example 1, l-ally1-l,2,5,6- tetrahydro-3-pyridylmethyl benzilic acid ester hydrochloride having a melting point of 143-144 C. was obtained.

EXAMPLE xvn Using the procedure of example I, 3-chloroallyl-l,2,5,6- tetrahydro-S-pyridylmethyl benzilic acid ester hydrochloride having a melting point of 135 C. was obtained.

EXAMPLE XVIII Using the procedure of example I, l-phenethyl-l,2,5,6- tetrahydro-3-pyridylmethyl benzilic acid ester hydrochloride having a melting point of l72-l 73 C. was obtained.

EXAMPLE XIX Using the procedure of example I, l-ethyl-l,2,5,6- tetrahydro-3-pyridyirnethyl-a-cyclohexyl-a-phenyl-acetic acid ester hydrochloride having a melting point of 203-204 C. was obtained.

EXAMPLE XX Using the procedure of example I, l-ethyl-l,2,5,6- tetrahydro-3-pyridylmethyl l-phenylcyclopentane-carboxylic acid acid ester hydrochloride having a melting point of 143- l45 C. was obtained.

EXAMPLE XXI Using the procedure of example I, l-ethyl-l,2,5,6- tetrahydro-3-pyridylmethyl-i-phenylcyclohexane carboxylic acid ester hydrochloride melting at l86-l88 C. was obtained.

EXAMPLE XXII Using the procedure of example I, l-BPcyanoethyl-l,2,5,6- tetrahydro-3-pyridylrnethyl benzilic acid ester hydrochloride melting at l46-l48 C. was obtained.

EXAMPLE XXIII Using the procedure of example I, l-propargyl-l,2,5,6- tetrahydro-3-pyridylrnethyl benzilic acid ester hydrochloride melting at l42-i 43 C. was obtained.

EXAMPLE XXIV Using the procedure of example I, l-ethyl-i,2,5,6 tctrahydro-B-pyridylmethyl hexahydrobenzilic acid ester hydrochloride melting at 2 l -2 1 2 C. was obtained.

EXAMPLE XXV Using the procedure of example I, l-n-hexyl-l,2,5,6- tetrahydro-S-pyridylmethyl hexahydrobenzilic acid ester hydrochloride melting at l32-l 35 C. was obtained.

EXAMPLE XXVI Using the procedure of example I, l-ethyll,2,5,6- tetrahydro-3-pyridylmethyl-a,a-diphenyl acetic acid ester hydrochloride melting at l98-200 C. was obtained.

PHARMACEUTICAL EXAMPLES Example A Sugar-Coated Tablets The mixture ofthe active ingredient with lactose and corn starch was granulated with a 10 percent aqueous gelatin solution through a screen of 1 mm. mesh size, dried at 40 C. and triturated once more through a screen. The granulate thus ob tained was mixed with magnesium stearate and pressed into cores. The coresthus obtained were coated with a shell in the usual manner. the latter being attached to the cores with an aqueous suspension of sugar, titanium dioxide, talcum and gum arabic. The finished sugar coated tablets were polished with beeswax to obtain sugar coated tablet weighing l00 mg.

Example 8 Tablets I ethyl-l .2 .5.6-tetrahydro-3-pyridylmethyl benzilic acid estar'HCl 3.0 mg. lactose 50.0 mg. corn starch 32.0 mg. soluble starch 4.0 mg. magnesium stearate l.0 mg.

Total 90.0 mg. 2225522! The active ingredient and magnesium stearate were granulated with an aqueous solution of thevsoluble starch. The granulate was dried and intimately mixed with lactose and corn starch. The mixture was'then pressed into tablets of mg. of weight, each containing 3 mg. of active ingredient.

Example C Suppositories l suppository contains: l-ailyll ,2.5.6-tetrahydro-3-pyridylmethyl benzilic acid eater-HCI 5.0 mg. suppository mass l,695.0 mg. Total l,700.0 mg.

Preparation The finely pulverized active substance was stirred into the molten suppository mass cooled to 40 C. with the aid of an immersion homogenizer. At 35 C., the mass was poured into slightly precooied molds.

Example D Ampuls pyridyl-methyl benzilic acid esterl-lCl 2.0 mg. sodium chloride 3.0 mg. distilled water 2.0 ml.

Preparation or scope thereof.

We claim: l Acom pound of the formula r. air oil-0 11f" CoHs wherein R is straight alkyl of two to 10 carbon atoms, branched alkyl of three to five carbon atoms, alkenyl of two to three carbon atoms, halo-alkenyl of two to three carbon atoms, alkinyl of two to three carbon atoms. cycloalkyl of three to six carbon atoms or phenyl-(alkyl of one to two carbon atoms),

R, is hydrogen, methyl, hydroxyl or chlorine,

R, is hydrogen, phenyl or cycioalkyl of five to six carbon atoms, and

R and R together with each other and the carbon atom to which they are attached, are cyclopentyl or cyclohexyl, or a nontoxic, pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 13, wherein R is alkyl of thereoftwo to six carbon atoms or allyl, R is hydroxyl and R, is pheny 3. A compound according to claim 13, which is l-n-hexyll,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester or a nontoxic, pharmaceutically acceptable acid addition salt thereof,

8. A compound according to claim 1, wherein R is alkyl of two to 10 carbon atoms, allyl, chloroallyl, propargyl or phenethyl,

R is hydrogen or hydroxyl,

R, is phenyl, cyclopentyl or cyclohexyl, and

R, and R together with each other and the carbon atoms to which they are attached, are cyclopentyl or cyclohexyl.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent-No. 3, 7,775 Dated Dec. 1M, 1971- 'mvefitofls) Hans-Hugo .Hubner; Gerhard Walther; Karl Zeile;

' Helmut Wick; and Klaus Stockhaus It is certified that error appears in the above-identified patent and that said Letters Patent are herebycorrected as shown below:

[54] --ACID ESTERS-- should be added to the title. Col. 1- --ACID ESTERS-- should be added to the title.

Col. 3- correct the formula to read I JCHZ-OH +2 Hal Col. 3, line 50' correct the spelling of "undesirable".

Col. 8, lines 52; 63, 64 correct the spelling of "ampoules".

Claims 2, 3,' 5, 6, 7, first u e of-each I "claim 13' should read --claim l--.

- Signed and sealed-this 24th day of October 1972 (SEAL) Attest:

EDWARD M.FLETCHER,JR.Y ROBERT GOTTSCHALK Atte-sting. Officer Commissioner of Patents 

2. A compound according to claim 13, wherein R is alkyl of two to six carbon atoms or allyl, R1 is hydroxyl and R2 is phenyl.
 3. A compound according to claim 13, which is 1-n-hexyl-1,2,5, 6-tetrahydro-3-pyridylmethyl benzilic acid ester or a nontoxic, pharmaceutically acceptable acid addition salt thereof.
 4. A compound according to claim 13, which is 1-ethyl-1,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester or a nontoxic, pharmaceutically acceptable acid addition salt thereof.
 5. A compound according to claim 13, which is 1-n-amyl-1,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester or a nontoxic, pharmaceutically acceptable acid addition salt thereof.
 6. A compound according to claim 13, which is 1-phenylethyl-1,2, 5,6-tetrahydro-3-pyridylmethyl benzilic acid ester or a nontoxic, pharmaceutically acceptable acid addition salt thereof and its quaternary ammonium salts.
 7. A compound according to claim 13, which is 1-allyl-1,2,5,6-tetrahydro-3-pyridylmethyl benzilic acid ester or a nontoxic, pharmaceutically acceptable acid addition salt thereof.
 8. A compound according to claim 1, wherein R is alkyl of two to 10 carbon atoms, allyl, chloroallyl, propargyl or phenethyl, R1 is hydrogen or hydroxyl, R2 is phenyl, cyclopentyl or cyclohexyl, and R1 and R2, together with each other and the carbon atoms to which they are attached, are cyclopentyl or cyclohexyl. 